The invasive behavior of oral squamous cell carcinoma (OSCC) requires coordinated cellular events including degradation of the extracellular matrix (ECM) and the acquisition of motility. Altered expression of cadherins, transmembrane proteins that promote cell-cell contacts, has been associated with progression of OSCC. In many tumors, loss of E-cadherin or aberrant expression of N-cadherin has been shown to correlate with increased invasive behavior. Production of ECM degrading proteases, for example matrix metalloproteinases (MMPs), is also an early event in the malignant progression. In OSCC, a correlation between enhanced expression of MMP-2 (gelatinase A), MMP-9 (gelatinase B), membrane-type 1 MMP (MT1-MMP) and tumor progression has been described. Our data demonstrate that E-cadherin can regulate the expression of MMP-2 and MMP-9. Moreover, we have shown that disruption of cell-cell adhesions can induce MMP-dependent cellular invasion. Furthermore, our preliminary data demonstrate the involvement of phosphatidylinositol 3-kinase (PI3-kinase) in the E-cadherin-mediated regulation of MMPs. Based on these results, it is the working hypothesis of this proposal that a functional link between cell-cell adhesion and proteolysis regulates OSCC invasive behavior. Specifically, we propose that cadherin engagement modulates MMP expression and consequently controls cell motility and invasion. To test this hypothesis, we will assess the role of E- and N-cadherin in the regulation of MMP expression. Immunohistochemical and biochemical analysis of tumor tissues will be employed to evaluate the expression patterns of E- and N-cadherins, and MMPs. The biochemical pathways that are involved in the regulation of MMPs by E- and N-cadherin will then be evaluated. The long-term goal of the proposed research is to provide a more detailed understanding of the functional link between cell-cell adhesion and proteolysis and the contribution of this interplay to regulation of metastasis.